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A computational approach to evaluate the androgenic affinity of iprodione, procymidone, vinclozolin and their metabolites.

Galli CL, Sensi C, Fumagalli A, Parravicini C, Marinovich M, Eberini I - PLoS ONE (2014)

Bottom Line: We computed the affinity for all the selected molecules following a computational approach based on molecular modelling and docking.Moreover, a different sensitivity concerning AR LBD was computed for the tested species (rat being the least sensitive of the three).The introduction of in silico approaches to evaluate hazard can accelerate discovery and innovation with a lower economic effort than with a fully wet strategy.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italia.

ABSTRACT
Our research is aimed at devising and assessing a computational approach to evaluate the affinity of endocrine active substances (EASs) and their metabolites towards the ligand binding domain (LBD) of the androgen receptor (AR) in three distantly related species: human, rat, and zebrafish. We computed the affinity for all the selected molecules following a computational approach based on molecular modelling and docking. Three different classes of molecules with well-known endocrine activity (iprodione, procymidone, vinclozolin, and a selection of their metabolites) were evaluated. Our approach was demonstrated useful as the first step of chemical safety evaluation since ligand-target interaction is a necessary condition for exerting any biological effect. Moreover, a different sensitivity concerning AR LBD was computed for the tested species (rat being the least sensitive of the three). This evidence suggests that, in order not to over-/under-estimate the risks connected with the use of a chemical entity, further in vitro and/or in vivo tests should be carried out only after an accurate evaluation of the most suitable cellular system or animal species. The introduction of in silico approaches to evaluate hazard can accelerate discovery and innovation with a lower economic effort than with a fully wet strategy.

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Related in: MedlinePlus

Molecular surface of the binding site and filling dummy atoms in the zebrafish AR LBD model, side (A) and top (B) view.
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pone-0104822-g002: Molecular surface of the binding site and filling dummy atoms in the zebrafish AR LBD model, side (A) and top (B) view.

Mentions: The homology model of the zebrafish AR LBD was built using as template 1T7R, the crystal structure of chimpanzee AR LBD (66% sequence identity). Figure S1 in File S1 shows the alignment used for carrying out the modelling procedure. Ten independent models were built and refined, and the one top scoring according to the electrostatic solvation energy was selected. The presence of a well-defined binding site, shown in Figure 2, was probed through the MOE Site Finder program. The same approach was applied to human and rat AR LBD crystals. Table 1 reports the binding site scores for the three receptor structures and lists the residues lining each of them. Figure 3 shows the global alignment of the investigated AR LBD; the residues in the binding sites are highlighted. Finally, after a structural superposition, the global and the binding site RMSD values were computed both for α-carbons and for whole residues of the three AR LBD; data are summarized in Table 2.


A computational approach to evaluate the androgenic affinity of iprodione, procymidone, vinclozolin and their metabolites.

Galli CL, Sensi C, Fumagalli A, Parravicini C, Marinovich M, Eberini I - PLoS ONE (2014)

Molecular surface of the binding site and filling dummy atoms in the zebrafish AR LBD model, side (A) and top (B) view.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4128724&req=5

pone-0104822-g002: Molecular surface of the binding site and filling dummy atoms in the zebrafish AR LBD model, side (A) and top (B) view.
Mentions: The homology model of the zebrafish AR LBD was built using as template 1T7R, the crystal structure of chimpanzee AR LBD (66% sequence identity). Figure S1 in File S1 shows the alignment used for carrying out the modelling procedure. Ten independent models were built and refined, and the one top scoring according to the electrostatic solvation energy was selected. The presence of a well-defined binding site, shown in Figure 2, was probed through the MOE Site Finder program. The same approach was applied to human and rat AR LBD crystals. Table 1 reports the binding site scores for the three receptor structures and lists the residues lining each of them. Figure 3 shows the global alignment of the investigated AR LBD; the residues in the binding sites are highlighted. Finally, after a structural superposition, the global and the binding site RMSD values were computed both for α-carbons and for whole residues of the three AR LBD; data are summarized in Table 2.

Bottom Line: We computed the affinity for all the selected molecules following a computational approach based on molecular modelling and docking.Moreover, a different sensitivity concerning AR LBD was computed for the tested species (rat being the least sensitive of the three).The introduction of in silico approaches to evaluate hazard can accelerate discovery and innovation with a lower economic effort than with a fully wet strategy.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italia.

ABSTRACT
Our research is aimed at devising and assessing a computational approach to evaluate the affinity of endocrine active substances (EASs) and their metabolites towards the ligand binding domain (LBD) of the androgen receptor (AR) in three distantly related species: human, rat, and zebrafish. We computed the affinity for all the selected molecules following a computational approach based on molecular modelling and docking. Three different classes of molecules with well-known endocrine activity (iprodione, procymidone, vinclozolin, and a selection of their metabolites) were evaluated. Our approach was demonstrated useful as the first step of chemical safety evaluation since ligand-target interaction is a necessary condition for exerting any biological effect. Moreover, a different sensitivity concerning AR LBD was computed for the tested species (rat being the least sensitive of the three). This evidence suggests that, in order not to over-/under-estimate the risks connected with the use of a chemical entity, further in vitro and/or in vivo tests should be carried out only after an accurate evaluation of the most suitable cellular system or animal species. The introduction of in silico approaches to evaluate hazard can accelerate discovery and innovation with a lower economic effort than with a fully wet strategy.

Show MeSH
Related in: MedlinePlus